Decellularized plant-derived vasculature-on-a-chip interacting with breast cancer spheroids to evaluate a dual-drug therapy

Abstract

Breast cancer progression is a complex process involving the primary tumor and its microenvironment supported by a vascular network. Multicellular spheroids closely mimic in vivo-like tumor conditions, paving the way for effective treatments. Although spheroid formation by simulated microgravity emerges as a promising technique for cancer spheroids, the lack of a perfusable vascular network still limits the evaluation of tumor progression. Recently, decellularized plant structures with hierarchically formed vasculatures similar to the human vascular system gained interest as engineered vascular networks. In this study, breast cancer spheroids co-cultured with endothelial cells were grown both under unit-gravity and simulated microgravity conditions, whereas vasculature was formed by the decellularization of spinach leaf. The optimized spheroids and plant-derived vasculature populated with endothelial cells were integrated into a microplatform, where fibroblasts were embedded into the extracellular matrix (ECM) to mimic the tumor microenvironment (TME). The vasculature-on-a-chip was used to assess the response of breast cancer spheroids to a combinatorial dose of Doxorubicin (DOX) and Bevacizumab (BMAB) treatment administered to circulating flow emulating intravenous administration. The developed platform offers a biomimetic model to recapitulate key aspects of breast cancer progression and evaluate the responses of both the tumor and the vasculature to chemotherapeutic drugs.